This invention pertains to the field of oxytocin and vasopressin antagonists.
In the field of obstetrics, one of the most important problems is the management of preterm labor. A significant number of the pregnancies progressing past 20 weeks of gestation experience premature labor and delivery which is a leading cause of neonatal morbidity and mortality.
It has recently been proposed that a selective oxytocin antagonist would be the ideal tocolytic agent. In the last few years, evidence has accumulated to strongly suggest that oxytocin is the physiological initiator of labor in several mammalian species including humans. Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may, in addition, be important in the cervical ripening process. By these mechanisms, the process of labor (term and preterm) is initiated by a heightened sensitivity of the uterus to oxytocin, resulting in part by a well documented increase in the number of oxytocin receptors in this tissue. This `up-regulation` of oxytocin receptors and enhanced uterine sensitivity appears to be due to trophic effects of rising plasma levels of estrogen towards term. By blocking both the direct (contractile) and indirect (enhanced prostaglandin synthesis) effects of oxytocin on the uterus, a selective oxytocin antagonist would likely be more efficacious for treating preterm labor than current regimens. In addition, since oxytocin at term has major effects only on the uterus, such a compound would be expected to have few, if any, side effects.
Vasopressin (also known as Antidiuretic Hormone, ADH) is a pituitary peptide hormone that is vital for the maintenance of proper water balance in animals and man. The antidiuretic effect of vasopressin concentrates the urine by increasing the reabsorption of water from the kidney filtrate. Thus, even under mild conditions of dehydration enhanced blood levels of vasopressin act to conserve water and control the proper osmolarity of the blood and extracellular fluids. Vasopressin also acts to contract vascular smooth muscle and may normally be involved in the maintenance of peripheral vascular resistance (McNeil, J. R., Can. J. Physiol Pharmacol 61: 1226-1235 (1983); Cowley, A. W., Quillen, E. W., and Skelton, M. M., Federation Proceedings 42: 3170-3176 (1983)).
Recent studies have led to the development of relatively potent and specific antagonists of the antidiuretic or pressor effects of vasopressin (Sawyer, W. H., and Manning, M., Federation Proceedings 43: 87-90 (1984)). Because of the prominent actions of vasopressin on renal and cardiovascular function, vasopressin antagonists are useful in the treatment of several conditions including congestive heart failure, hypertension, and states of edema. The salt-sparing, `water diuretic` activity of vasopressin antagonists would be particularly useful in the treatment of hyponatremia which can arise from a variety of conditions (Zerbe, R., Stropes, L., Robertson, G., Ann. Rev. Med. 31: 315-327 (1980)). The currently known vasopressin antagonists are peptide analogues of vasopressin (Huffman, W. H., Ali, F. E., Bryan, W. M. et al. J. Med Chem 28: 1759-1760 (1985)) and are, therefore, likely to be rapidly metabolized in vivo and to have little, if any, oral activity (Lynn, R. K., Straub, K. M., Landvatter, S. W., and Garvey, C. T., Federation Proceedings 45: 205 (1986); Kinter, L. B., Mann, W. A., Woodward, P., DePalma, D. and Brennan, F., Federation Proceedings 45: 649 (1986)).
It is, therefore, an object of the present invention to provide cyclic peptides and synthetic analogues which are antagonists of oxytocin and vasopressin and are useful as pharmaceutical agents. It is also an object of the present invention to provide processes for producing these cyclic peptides. It is a further object of the invention to provide a mixture of cyclic peptides of Formula I and its minor related components A, B, C, D, E, F and G produced by aerobic fermentation of the organism Streptomyces silvensis. Another object is to provide cultures of the organism Streptomyces silvensis ATCC No. 53525 or ATCC No. 53526 which are capable of producing the cyclic peptides and mixtures thereof. A still further object is to provide synthetic analogues of these cyclic peptides.